Adolescence is a period of substantial neuroplasticity in stress NFIL3

Adolescence is a period of substantial neuroplasticity in stress NFIL3 regulatory neurocircuits. (HPA) axis in response to a novel stressor and increased immobility in the forced swim test. Blunted HPA axis responses were accompanied by reduced vasopressin mRNA expression in the paraventricular nucleus of the hypothalamus (PVN) suggesting decreased central drive. Adolescent females tested immediately after CVS did not exhibit differences in stress reactivity or immobility in the forced swim test despite evidence for enhanced central HPA axis drive (increased CRH mRNA expression in PVN). Ciproxifan Overall our study demonstrates that exposure to chronic stress in adolescence is sufficient to induce lasting changes in neuroendocrine drive and behavior potentially altering the developmental trajectory of stress circuits as female rats age into adulthood. 1 INTRODUCTION Onset of stress-related psychopathologies (e.g. depression) often occurs during late adolescence (Kessler et al. 2003 Lewinsohn et al. 1999 and is frequently precipitated by chronic stress (Ge et al. 2006 Goodyer et al. 1998 Ham and Larson 1990 Larson et al. 1990 Rudolph and Hammen 1999 Women are twice as likely as men to develop stress-related psychopathologies (Kessler et al. 1993 Kuehner 2003 indicating that sex is an important determinant of disease susceptibility. Recent rodent studies indicate that exposure to chronic stress during adolescence results in greater and longer-lasting changes in behavior and hypothalamo-pituitary-adrenocortical (HPA) axis function in females than in males (Bourke and Neigh 2011 McCormick et al. 2008 Taken together these findings suggest that exposure to chronic stress during the period of adolescence can lead to changes in endocrine and brain function that may predispose individuals females in particular to the development of stress-related psychopathologies. Adolescence is an important developmental time-point in brain development and is a period of active neuroplasticity in important neural pathways involved in stress regulation and HPA axis function (Andersen and Teicher 2008 Andersen 2003 Eiland and Romeo 2013 The period of adolescence in rats can be subdivided into early or pre-pubertal adolescence (pnd 27– 34) mid or pubertal adolescence (pnd 34– 46) and late or post-pubertal adolescence (pnd 47 – 59). These time periods are characterized by differential development of critical stress-regulatory regions including the hippocampus prefrontal cortex (PFC) and the amygdala. Prior studies indicate exaggerated and prolonged HPA axis stress responses in (male and female) adolescents relative to adults (Romeo et al. 2004 2004 suggesting a connection between the relative immaturity of stress circuits and enhanced HPA axis drive. Moreover male rats exposed to a chronic variable stress (CVS) paradigm during late adolescence are particularly sensitive to the somatic and neuroendocrine effects of chronic stress compared to early-adolescent rats (Jankord et al. 2011 indicating that late adolescence the period encompassing final maturation of PFC-amygdala connections (Andersen and Teicher 2008 Andersen 2003 may represent a time period of stress hypersensitivity. Together these findings suggest a potential amplification of the impact of stress on neural targets during this period of life which may have lasting consequences on stress reactivity (HPA axis function behavior) later in life. Despite knowledge that the adolescent Ciproxifan period is vulnerable to the effects of stress and that females seemed to be preferentially susceptible to stress-related diseases (Kessler et al. 1993 little is known about the mechanisms by which stress may alter the development of the female adolescent brain. The purpose of this study was to assess the long-term impact of adolescent exposure Ciproxifan to chronic stress on stress reactivity and stress-related behaviors in female rats. 2 MATERIALS AND METHODS 2.1 Animals Twelve timed-pregnant (E10) Sprague-Dawley rats were obtained from Harlan (Indianapolis IN USA). Pups were born approximately one week after the arrival of the pregnant dams and remained with their mothers until weaning at pnd 25 of age. Only female rats were used for this experiment. At weaning littermates were separated by sex and housed two per cage. Rats were divided into four experimental groups: CVS adolescent (adolescent CVS exposure tested in adolescence n=12) control adolescent (n=10) CVS adult (adolescent CVS exposure tested in adulthood n=12) control Ciproxifan adult (n=10). In order to.